Protein phosphorylation/dephosphorylation is an important regulatory mechanism that controls many key physiological processes. Numerous pathogens successfully use kinases and phosphatases to internalize, replicate, and survive, modifying the host's phosphorylation profile or signal transduction pathways. Multiple phosphatases and kinases from diverse bacterial pathogens have been implicated in human infections before. In this work, we have identified and characterized the dual specificity protein/lipid phosphatase LmDUSP1 as a novel virulence factor governing Leishmania mexicana infection. The LmDUSP1-encoding gene (LmxM.22.0250 in L. mexicana) has been acquired from bacteria via horizontal gene transfer. Importantly, its orthologues have been associated with virulence in several bacterial species, such as Mycobacterium tuberculosis and Listeria monocytogenes. Leishmania mexicana with ablated LmxM.22.0250 demonstrated severely attenuated virulence in the experimental infection of primary mouse macrophages, suggesting that this gene facilitates Leishmania pathogenicity in vertebrates. Despite significant upregulation of LmxM.22.0250 expression in metacyclic promastigotes, its ablation did not affect the ability of mutant cells to differentiate into virulent stages in insects. It remains to be further investigated which specific biochemical pathways involve LmDUSP1 and how this facilitates the parasite's survival in the host. One of the interesting possibilities is that LmDUSP1 may target host's substrate(s), thereby affecting its signal transduction pathways.

Biology Centre Institute of Parasitology Czech Academy of Sciences 37005 České Budejovice Czech Republic

Department of Parasitology Faculty of Science Charles University 12844 Prague Czech Republic

Federal Research and Clinical Center of Physical Chemical Medicine of Federal Medical Biological Agency 119435 Moscow Russia

Life Sciences Research Centre Faculty of Science University of Ostrava 71000 Ostrava Czech Republic

Martsinovsky Institute of Medical Parasitology Tropical and Vector Borne Diseases Sechenov University 119435 Moscow Russia

University of South Bohemia Faculty of Sciences 37005 České Budejovice Czech Republic

Zoological Institute of the Russian Academy of Sciences 199034 St Petersburg Russia

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Ku80 is involved in telomere maintenance but dispensable for genomic stability in Leishmania mexicana

Catalase impairs Leishmania mexicana development and virulence

Diverse telomeres in trypanosomatids

Genome Analysis of Endotrypanum and Porcisia spp., Closest Phylogenetic Relatives of Leishmania, Highlights the Role of Amastins in Shaping Pathogenicity

Protein methyltransferase 7 deficiency in Leishmania major increases neutrophil associated pathology in murine model

Large-Scale Phylogenetic Analysis of Trypanosomatid Adenylate Cyclases Reveals Associations with Extracellular Lifestyle and Host-Pathogen Interplay

Suicidal Leishmania